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Lessons learned from an unusual case of severe hypoglycemia

  • Istituto San Raffaele, Roma


We are hereby reporting on a woman with type 1 diabetes getting insulin, 4 shots a day, and referring to us for an episode of severe hypoglycemia occurred after vigorously rubbing a lipo-hypertrophy (LH). She had always injected insulin into an abdominal LH area but had never suffered from any hypoglycemic event (Hypo) during the last period. Nevertheless her history included frequent Hypos, mostly mild-to-moderate but sometimes severe and eventually ending into unconsciousness and her glycemic control was poor (HbA1c 8.3%, mean FPG 161 ± 22 mg/dl, mean PPG 218 ± 51 mg/dl, glycemic variability (106 ± 44 mg/dl). In fact, all of a sudden she rubbed vigorously the LH area trying to get rid of the abdominal skin thickening and soon after a severe Hypo occurred causing her to need for emergency medical assistance. When back at home, she corrected her technique and carefully refrained from inject insulin into the LH so that after six months the lesion disappeared, glycemic control improved and no Hypo occurred any more. Based on the recent publication reporting on a woman with a large LH consisting of thickened skin surrounding some fluid containing insulin at concentrations 13 fold those in blood, we hypothesize that such severe depended on massive insulin release from rubbed skin stores into the blood stream.
Case Report
Lessons learned from an unusual case of severe hypoglycemia
M.R. Improta
, F. Strollo
S. Gentile
, on behalf AMD-OSDI Study Group on Injection Technique
Nefrocenter Research Network, AID Stabia, Casrellammare di Stabia, Naples, Italy
Endocrinology and Diabetes, San Raffaele Termini Institute, Rome, Italy
Campania University ‘‘Luigi Vanvitelland Nefrocenter Research Network, Naples, Italy
article info
Article history:
Received 23 December 2018
Accepted 18 January 2019
We are hereby reporting on a woman with type 1 diabetes getting insulin, 4 shots a day, and referring to
us for an episode of severe hypoglycemia occurred after vigorously rubbing a lipo-hypertrophy (LH). She
had always injected insulin into an abdominal LH area but had never suffered from any hypoglycemic
event (Hypo) during the last period. Nevertheless her history included frequent Hypos, mostly mild-to-
moderate but sometimes severe and eventually ending into unconsciousness and her glycemic control
was poor ( HbA1c 8.3%, mean FPG 161 ±22 mg/dl, mean PPG 218 ±51 mg/dl, glycemic variability
(106 ±44 mg/dl). In fact, all of a sudden she rubbed vigorously the LH area trying to get rid of the
abdominal skin thickening and soon after a severe Hypo occurred causing her to need for emergency
medical assistance. When back at home, she corrected her technique and carefully refrained from inject
insulin into the LH so that after six months the lesion disappeared, glycemic control improved and no
Hypo occurred any more. Based on the recent publication reporting on a woman with a large LH con-
sisting of thickened skin surrounding some uid containing insulin at concentrations 13 fold those in
blood, we hypothesize that such severe depended on massive insulin release from rubbed skin stores
into the blood stream.
©2019 Published by Elsevier Ltd on behalf of Diabetes India.
1. Case history
A 35 year old lady who had suffered from Type 1 diabetes
mellitus (T1DM) for ten years reported to our clinic. With a 154 cm
height, and a 56 kg weight (BMI 23.3 kg/m
), she was on a basal-
bolus regimen consisting of 3 pre-meal lispro injections (18 I.U. as
a whole) and a bedtime long-acting analogue administration (15
I.U. glargine). One year before her HbA1c was 7.1% (56 mmol/mol)
and during the last month her mean glucose levels were
126 ±15 mg/dl before meals and 189 ±23 mg/dl 2 h after, being
glycemic variability (GV dened according to Giorda et al., 2015 [1])
68 ±18 mg/dl. Her lipids, creatinine, urate, transminases, bilirubin,
blood cell and urine counts, blood pressure and heart rate (120/
80 mmHg and 80 bpm, respectively), as well as, physical exami-
nation were normal. No eye, kidney or peripheral/autonomic nerve
complications were present. No hypoglycemic event (Hypo)
occurred during the last month either, as opposed to several
previously recorded, even severe, Hypos, eventually ending into
2. Anecdotal report
When asked how many and severe her Hypos had been
during the last 2 years, she said her Hypo rate was about twice a
week but she almost never became unconscious and anyway got
immediately better after ingesting some food or glucose despite
having to face quite often and during the previoous 6 months
she experienced four severe Hypos, the last one causing un-
consciousness (T-6). Her husband, who was there at the moment
and assisted her, helped us get a narrative of the episode: it was
summer and, due to her strong desire to wear a bikini, she tried
to get rid of a swelling to the right of her navel which, being as
big as a mandarin, was easily seen by anybody. She therefore
used a soothing cream to rub it long and deeply enough to get
weak in her lower limbs and soon develop tremors and un-
consciousness. In a recue effort, her husband immediately
checked her capillary glucose and found very low levels, i.e.
35 mg/dl. Being unconscious, she could neither swallow nor get
*Corresponding author.
E-mail address: (S. Gentile).
Contents lists available at ScienceDirect
Diabetes &Metabolic Syndrome: Clinical Research &Reviews
journal homepage:
1871-4021/©2019 Published by Elsevier Ltd on behalf of Diabetes India.
Diabetes &Metabolic Syndrome: Clinical Research &Reviews 13 (2019) 1237e1239
anything in her nose through a syringe, so he tried to perform
an intramuscular glucagon injection but unfortunately the latter
had got one month outdated in the refrigerator (it had been
kept there for a long time waiting for any - never-occurring -
severe Hypos). He then called the emergency number 118:
within a few minutes the health care personnel arrived and took
prompt steps by conrming the diagnosis and infusing 40 ml of
a highly concentrated glucose solution (33%) followed immedi-
ately by 500 ml of a less concentrated one (10%) into her
brachial vein. The patient took about 30 min to gradually regain
consiousness and glucose levels progressively recovered until
getting steadily normal so that there was no need for hospital-
ization. Accurate anamnestic investigations ruled out any insulin
administration errors, food intake variations, incongruous exer-
cise bouts or gastrointestinal symptoms including vomiting and
She provided us with capillary glucose recordings from 6
months before the reported accident (T-6) and from the following
ones until the present visit (Tþ6). Mean and SD values are reported
in Table 1 and Hypo monthly rate in Fig. 1.
The clinical trend proved to be completely different as all
metabolic parameters improved signicantly, severe Hypos dis-
appeared and mild to moderate Hypos progressively declined
during the second semester. An interesting accompanying phe-
nomenon was also observed: insulin requirement decreased by
about 15% during the post-accident period.
3. Clinical considerations
1. Taken together, symptoms preceding and accompanying the
unconsciousness episode, capillary glucose levels observed
during the accident and the fast responsivity to intravenous
glucose infusion point beyoing doubt to an episode of severe
2. The severe Hypo has to be dened as unexplained because no
common factors eventually leading to hypoglycemia were
identied [1,2].
3. The main cause of unexplained hypoglycemia is represented by
insulin injection into LH nodules [2,3].
4. The patient admitted she had been vigurously rubbing a
swelling close to her navel where she had repeatedly injected
insulin for months.
5. In agreement with literature reports, repeated insulin injection
into the same site and the disappearance of the swelling during
the post-accident semester strongly suggest the swelling to be
due to LH which in fact vanished with the change in injection
strategies described by the patient [3,4].
4. Additional medical history
Further investigations on a possible causal relationship between
rubbing the swelling and experiencing a severe Hypo immediately
after got us to know that the patient:
1. Did not rotate injection sites correctly
2. Repeatedly used the same needle
3. Often injected ice-cold insulin and
4. Did not feel cold when doing so
5. Did not feel any ache or burning after injection
6. Reversed her above mentioned behaviour (which is known to
cause LH) after the accident
Table 1
Comparison between mean values (±SD) of FPG, PPG, GV, HbA1c and the rate of HYPOs by severity during the 6 months before and after the accident.
FPG mg/dl (M±SD) PPG mg/dl (M±SD) GV pre/post meal (mg/dl) (M ±DS) HbA1c (%) Severe HYPOS in 6 months Symptomatic HYPOs in 6 months
T6 161 ±22 218 ±51 106 ±44 8.3 4 26
Tþ6 126 ±15 189 ±23 68 ±18 7.1 0 6
p<0.05 <0.05 <0.05 <0.01
M¼mean value; SD ¼standard deviation; FPG ¼fasting plasma glucose; PP ¼post-prandial plasma glucose; GV ¼glucose variability.
Fig. 1. Monthly Hypo rates before and after the accident occurred in July. Arrows point to severe hypos and the thick arrow points to the very severe one occurred in July and
described in this case story.
M.R. Improta et al. / Diabetes &Metabolic Syndrome: Clinical Research &Reviews 13 (2019) 1237e12391238
5. Lessons learned from the clinical case
In our view it is doubtless that the presence of an abdominal
swelling, which the patient preferred to inect into all the time, had
had a key role in the genesis of the above described accident. Based
on the anamnestic nding of many factors known to case LH [3], as
well as, both the disappearance of severe Hypos and the dramatic
decrease in the rate of non-severe Hypos after refraining for six
months from injecting insulin into the interested area, such
swelling could only reect the presence of LH [4,5].
Now, the reason why the described Hypo had been so severe
deserves a convincing explanation. The relationship between Hypos
and LH areas has been known for a long time and in fact a quite high
rate of mostly mild to moderate Hypos appeared in our patients
history but that was the very rst time such a severe Hypo occurred
in her ten year disease duration [2,3,5]. The effects of vigurous rub-
bing cannot be underestimated either in consideration of a recent
report in the literature: a very large area characterized by ultrasound
as a partially cystic LH lesion was found to contain insulin at con-
centrations 13 fold those in blood [6]. This supports the hypothesis
that rubbing represented a mechanical action eventually inducing
massive insulin releae into the blood stream. The time relationships
between the two events is also in agreement with such hypothesis
and with the national guidelines indications strongly discouraging
post-injection skin rubbing in both healthy and LH areas [7].
5.1. Limitations
Our hypothesis, despite being based on sound indirect consid-
erations, is only speculative because it lacks any indisputable
objective support.
Conicts of interest
The Authors declare no conicts of interest.
*Members of the Study Group. Coordinator: Gentile S. Collabo-
rators: Botta A, Cucco L, De Rosa N, De Riu S, Garrapa G, Gentile L,
Grassi G, Lalli C, Lo Grasso G, Marcone TM, Speese K, Sudano M, Tatti
P, Tonutti L. Chiandetti R. A special thanks is due to the members of
the group for the critique reading of the manuscript. The paper was
supported by an unconditioning special grant from AMD (Asso-
ciazione Medici Diabetologi).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
[1] Giorda CB, Ozzello A, Gentile S, Aglialoro A, Chiambretti A, Baccetti F,
Gentile FM, Lucisano G, Nicolucci A, Rossi MC, HYPOS-1 Study Group of AMD.
Incidence and risk factors for severe and symptomatic hypoglycemia in type 1
diabetes. Results of the HYPOS-1 study. Acta Diabetol 2015 Oct;52(5):845e53. Epub 2015 Feb 12.
[2] Strollo F, Guarino G, Armentano V, et al. On behalf of AMD-OSDI Italian Study
Group on Injection Techniques. Unexplained hypoglycaemia and large glycae-
mic variability: skin lipohypertrophy as a predictive sign. Diabetes Res Open J
[3] Blanco M, Hern
andez MT, Strauss KW, Amaya M. Prevalence and risk factors of
lipohypertrophy in insulin-injecting patients with diabetes. Diabetes Metab
2013 Oct;39(5):445e53. Epub
2013 Jul 22.
[4] Grassi G, Scuntero P, Trepiccioni R, Marubbi F, Strauss K. Optimizing insulin
injection technique and its effect on blood glucose control. J Clin Translat
Endocrinol 2014;1:145e50.
[5] Gentile S, Agrusta M, Guarino G, et al. Metabolic consequence of incorrect in-
sulin administration techniques in aging subjects with diabetes. Acta Diabetol
[6] Gentile S, Strollo F, Corte TD, Marino G, Guarino G. Italian Study Group on In-
jection Techniques. Skin complications of insulin injections: a case presentation
and a possible explanation of hypoglycaemia. Diabetes Res Clin Pract 2018
Apr;138:284e7. Epub 2018 Feb 8.
[7] AMD-SID. Standard di cura del diabete mellito AMD-SID.
M.R. Improta et al. / Diabetes &Metabolic Syndrome: Clinical Research &Reviews 13 (2019) 1237e1239 1239
... Several ''suggestions" lacking any scientific evidence in favor of soothing cremes and massage are also available on the web. However, as from a case report published by our group in this journal, thermic and mechanic effects of massage can even turn out to be dangerous because of eventually occurring untimely release of LH-stored insulin into the bloodstream, and consequent severe unexpected hypoglycemic events [5]. Chromolyn utilization, mostly intended for atrophic dystrophies, suffers limited research experience and, therefore, is not expected to be of any help as of today [6]. ...
... An intensive training on correct LH detection and insulin injection techniques prevented her from injecting insulin into LHs any longer and stopped the episodes of SeH, while even reducing her daily doses by [ 25%. The second case was another woman with an abdominal LH referred to our unit for frequent unexplained HE [41,42]. Wanting to wear a bikini when going to the beach, one morning she tried to get rid of her ugly nodule by massaging it with soothing emollient ointments, then she suddenly woke up in the hospital emergency room after a SHE; her husband confirmed that the above-mentioned LH had been the site of her last insulin injection. ...
Full-text available
IntroductionLipohypertrophies (LHs) due to incorrect insulin injection techniques have been described in the literature for decades. Their rate averages 38%, but this is still controversial because of the vast range reported by different publications, most of which fail to describe the selected detection protocol and therefore are not entirely reliable. We still need to identify the real LH rate, and only consistently using a standardized method in a large cohort of insulin-treated (IT) patients make this possible.Methods Our group performed thorough clinical skin examinations on patients suffering from type 2 diabetes mellitus (T2DM): 1247 IT T2DM outpatients were examined according to a standardized protocol, previously published elsewhere, as well as an ultrasound scan of the same skin areas to assess the degree of concordance between the two methods and to evaluate the demographic, clinical, and behavioral risk factors (RF) as well as metabolic consequences of identified LHs.ResultsThe concordance between the two methods was 99%. Identified risk factors for LHs were needle reuse, failure to rotate injection sites, and ice-cold insulin injections. High HbA1c values, wide glycemic variability, and longstanding proneness to hypoglycemia with a high rate of ongoing hypoglycemic events proved to be significantly associated with LHs, too; the same applied to cardiovascular and renal complications as well as to living alone and being retired.Conclusions Based on a strict well-structured methodology, our data confirmed what has already been reported in the literature on factors leading to, or associated with, LHs and, for the first time in adults, indicated cryotrauma from ice-cold insulin injections and specific social conditions as factors facilitating LH occurrence. HCPs should therefore plan a yearly clinical examination of all injection sites to improve patient quality of life through better glucose control and a reduced rate of hypoglycemic events.Trial RegistrationTrial registration no. 127-11.01.2019, approved by the Scientific and Ethics Committee of Campania University “Luigi Vanvitelli,” Naples, Italy.
Full-text available
Hypoglycemia is common in type 1 diabetes mellitus (T1DM). We aimed to update the incidence of severe and symptomatic hypoglycemia and investigate several correlated factors. In this multicenter, observational retrospective study, the data of 206 T1DM patients from a sample of 2,229 consecutive patients seen at 18 diabetes clinics were analyzed. Sociodemographic and clinical characteristics, severe hypoglycemia in the past 12 months, and symptomatic hypoglycemia in the past 4 weeks were recorded with a self-report questionnaire and a clinical form during a routine visit. Poisson multivariate models were applied. A minority of patients accounted for the majority of both severe and symptomatic episodes. The incidence rate (IR) of severe hypoglycemia was 0.49 (0.40-0.60) events/person-years. The incidence rate ratio (IRR) was higher in patients with previous severe hypoglycemia (3.71; 2.28-6.04), neuropathy (4.16; 2.14-8.05), long duration (>20 years, 2.96; 1.60-5.45), and on polypharmacy (1.24; 1.13-1.36), but it was lower when a complication was present. The IR of symptomatic hypoglycemia was 53.3 events/person-years, with an IRR significantly higher among women or patients with better education, or shorter duration or on pumps. The IRR was lower in patients with higher BMI or neuropathy or aged more than 50 years. Fewer than 20 % of T1DM patients are free from hypoglycemia, with one in six having experienced at least one severe episode in the last year. The distribution is uneven, with a tendency of episodes to cluster in some patients. Severe and symptomatic episodes have different correlates and reflect different conditions.
Full-text available
Purpose The purpose of the study is to assess whether proper Injection Technique (IT) is associated with improved glucose control over a three month period. Methods Patients (N=346) with diabetes from 18 ambulatory centers throughout northern Italy who had been injecting insulin ≥ four years answered a questionnaire about their IT. The nurse then examined the patient’s injection sites for the presence of lipohypertrophy (LH), followed by an individualized training session in which sub-optimal IT practices highlighted in the questionnaire were addressed. All patients were taught to rotate sites correctly to avoid LH and were begun on 4mm pen needles to avoid intramuscular (IM) injections. They were instructed not to reuse needles. Results Nearly 49% of patients were found to have LH at study entry. After three months, patients had mean reductions in HbA1c of 0.58% (0.50%-0.66%, 95% CI), in fasting blood glucose of 14 mg/dL (10.2-17.8 mg/dL, 95% CI) and in total daily insulin dose of 2.0 IU (1.4-2.5 IU, 95% CI) all with p<0.05. Follow-up questionnaires showed significant numbers of patients recognized the importance of IT and were performing their injections more correctly. The majority found the 4 mm needle convenient and comfortable. Conclusions Targeted individualized training in IT, including the switch to a 4mm needle, is associated with improved glucose control, greater satisfaction with therapy, better and simpler injection practices and possibly lower consumption of insulin after only a three month period.
Full-text available
Only few insulin-treated (IT) people with diabetes mellitus (DM) reach the target due to poor compliance and/or to sedentary lifestyle and/or to inadequate treatment regimen. The latter may be also brought about by often overlooked factors including insulin injection into altered skin areas, often brought about by incorrect habits, namely needle reutilization or poor compliance to the suggestion to continuously rotate skin injection areas. The aim of our study was to evaluate the rate of skin lesions within the sites commonly used for insulin injection in our IT DM patients and to verify whether a short-acting insulin analogue yielded different metabolic effects when injected in altered vs. normal skin areas. One hundred and eighty well-trained IT people with type 1 and type 2 DM (64 ± 15 years of age) consecutively referring to our unit underwent a standard clinical examination involving an accurate skin inspection protocol meant at looking for any alterations eventually affecting all possible injection sites, including bruising, multiple needle pricks and lipodystrophic nodules (LN). They were also tested for HPLC HbA1c determination and asked to fill in a standard questionnaire on injection habits. Furthermore, seven male, T1DM glulisine-glargine basal-bolus-treated patients in this group were randomly injected 10 IU glulisine into either normal skin (NS) or an LN by a nurse before a standard, 405 kcal breakfast, for blood glucose and free insulin determination at 0, 30, 45, 60, 75, 90, 120 and 150 min. More lesions were found in people over sixty (P < 0.01) and in women (P < 0.05). A higher prevalence of HbA1c >7.5% was found in patients with lesions (with an O.R. of 3.74) and further confirmed by data obtained from head-to-head comparison of insulin injection into an LN and NS. In fact, injection into an LN proved to impair and slow down insulin absorption, resulting in a higher absolute value and a larger variability of blood glucose levels than those observed by utilizing NS. This suggests us to pay more attention to all aspects of patient-team relationship to try and obtain good metabolic control in all people with diabetes and even more in the elderly.
We are willing to report the case of a woman with type 2 diabetes treated with insulin, 4 shots a day, referring to us for 2 very large pigmented abdominal lipo-hypertrophy (LH) areas due to incorrect injection technique. The ultrasound examination showed the presence offluidwithin both LH lesions. Fluid examination showed insulin concentrations 13 times higher thancirculating ones. A6-month longstructured training on correct injection techniques normalized metabolic control and took rid of all sudden severe hypoglycemic episodes and the wide glycemic variability. In fact, both LH areas disappeared became softer and slightly smaller and got fluid-free. This is the first case documenting the presence of sort of an insulin reservoir within LH lesions and fluid reabsorption can explain the disappearance of hypoglycemic episodes and the improvement of glycemic control.
Our objective was to assess the frequency of lipohypertrophy (LH) and its relationship to site rotation, needle reuse, glucose variability, hypoglycaemia and use of insulin. The study included 430 outpatients injecting insulin who filled out a wide-ranging questionnaire regarding their injection technique. Then, a diabetes nurse examined their injection sites for the presence of LH. Nearly two-thirds (64.4%) of patients had LH. There was a strong relationship between the presence of LH and non-rotation of sites, with correct rotation technique having the strongest protective value against LH. Of the patients who correctly rotated sites, only 5% had LH while, of the patients with LH, 98% either did not rotate sites or rotated incorrectly. Also, 39.1% of patients with LH had unexplained hypoglycaemia and 49.1% had glycaemic variability compared with only 5.9% and 6.5%, respectively, in those without LH. LH was also related to needle reuse, with risk increasing significantly when needles were used>5 times. Total daily insulin doses for patients with and without LH averaged 56 and 41IU/day, respectively. This 15 IU difference equates to a total annual cost to the Spanish healthcare system of>€122 million. This was also the first study in which the use of ultrasound allowed the description of an "echo signature" for LH. Correct injection site rotation appears to be the critical factor in preventing LH, which is associated with reduced glucose variability, hypoglycaemia, insulin consumption and costs.